We and others have made the important observation that the incidence of COPD is higher among the HIV infected population compared to the non-HIV infected population. In particular, HIV-infected smokers appear to be susceptible to an emphysema phenotype characterized physiologically by diffusion impairment. Preliminary data suggests that there are altered protein expression patterns in extracellular vesicles (EV) among HIV-infected smokers with and without emphysema. These patterns implicate a number of biologic pathways that may be dysregulated in HIV-associated emphysema, including the oxidative stress response, anti-protease mechanisms and surfactant homeostasis. Preliminary data also demonstrates that deregulation of microRNAs (miRNAs) may be a key driver of biological pathways implicated in the pathogenesis of emphysema, including oxidative stress, TGF beta, Map Kinase and Wnt pathways. In this investigation we will build on these observations and propose to examine the relevance of EV based biomarkers by developing a functional miRNA signature for HIV associated emphysema. We will do this by the systematic examination and integration of both proteomic and miRNA patterns within EVs. To achieve this objective we will pursue the following specific aims: Specific Aim 1: To test the hypothesis that alterations in lung EV protein expression profiles associated with HIV-induced emphysema can be distinguished from those pathways associated with emphysema in the HIV- uninfected population. Specific Aim 2: To investigate if lung EV miRNA expression drives distinct biological networks identified through deregulated proteins contributing to the pathogenesis of HIV associated emphysema. Specific Aim 3: To test the hypothesis that circulating EV based biomarkers may be associated with increased risk of lung damage occurring in HIV-infected smokers. Successful completion of this project will inform our knowledge of HIV-related lung disease and may also provide important insight into emphysema pathobiology.